Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue

Rosenfeldt et al Cardiopulmonary Support and Physiology

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Coenzyme Q10 therapy before cardiac surgery improvesmitochondrial function and in vitro contractility ofmyocardial tissueFranklin Rosenfeldt, MD, FRACSa,b

Silvana Marasco, FRACSa

William Lyon, MBBSa

Michelle Wowk, BSc(Hons)a

Freya Sheeran, BA, BSc(Hons)a

Michael Bailey, MSc(Stats)b

Donald Esmore, FRACSa

Bruce Davis, FRACSa

Adrian Pick, FRACSa

Mark Rabinov, PhD, FRACSa

Julian Smith, MSurg, FRACSa

Phillip Nagley, PhD, DScc

Salvatore Pepe, PhDa

From The Cardiac Surgical Research Unit,Department of Cardiothoracic Surgery, Al-fred Hospital, the Baker Heart ResearchInstitute (Wynn Domain), and the Depart-ment of Surgery,a Monash University; theDepartment of Epidemiology and Preven-tative Medicine,b Monash University; andthe Department of Biochemistry and Mo-lecular Biology,c Monash University, Mel-bourne, Australia.

Supported by the National Heart Founda-tion of Australia and Blackmores AustraliaPty Ltd.

Received for publication Sept 3, 2003; re-visions requested March 15, 2004; acceptedfor publication March 25, 2004.

Address for reprints: Salvatore Pepe, PhD,Baker Heart Research Institute, PO Box6492, St Kilda Road Central, MelbourneVIC 8008, Australia (E-mail: [email protected]).

J Thorac Cardiovasc Surg 2005;129:25-32

0022-5223/$30.00

Copyright © 2005 by The American Asso-ciation for Thoracic Surgery

doi:10.1016/j.jtcvs.2004.03.034

Objectives: Previous clinical trials suggest that coenzyme Q10 might afford myo-cardial protection during cardiac surgery. We sought to measure the effect ofcoenzyme Q10 therapy on coenzyme Q10 levels in serum, atrial trabeculae, andmitochondria; to assess the effect of coenzyme Q10 on mitochondrial function; totest the effect of coenzyme Q10 in protecting cardiac myocardium against a standardhypoxia-reoxygentation stress in vitro; and to determine whether coenzyme Q10

therapy improves recovery of the heart after cardiac surgery.

Methods: Patients undergoing elective cardiac surgery were randomized to receiveoral coenzyme Q10 (300 mg/d) or placebo for 2 weeks preoperatively. Pectinatetrabeculae from right atrial appendages were excised, and mitochondria wereisolated and studied. Trabeculae were subjected to 30 minutes of hypoxia, andcontractile recovery was measured. Postoperative cardiac function and troponin Irelease were assessed.

Results: Patients receiving coenzyme Q10 (n � 62) had increased coenzyme Q10

levels in serum (P � .001), atrial trabeculae (P � .0001), and isolated mitochondria(P � .0002) compared with levels seen in patients receiving placebo (n � 59).Mitochondrial respiration (adenosine diphosphate/oxygen ratio) was more efficient(P � .012), and mitochondrial malondialdehyde content was lower (P � .002) withcoenzyme Q10 than with placebo. After 30 minutes of hypoxia in vitro, pectinatetrabeculae isolated from patients receiving coenzyme Q10 exhibited a greater re-covery of developed force compared with those in patients receiving placebo (46.3%� 4.3% vs 64.0% � 2.9%, P � .001). There was no between-treatment differencein preoperative or postoperative hemodynamics or in release of troponin I.

Conclusions: Preoperative oral coenzyme Q10 therapy in patients undergoing car-diac surgery increases myocardial and cardiac mitochondrial coenzyme Q10 levels,improves mitochondrial efficiency, and increases myocardial tolerance to in vitro
hypoxia-reoxygenation stress.
The Journal of Thoracic and Cardiovascular Surgery ● Volume 129, Number 1 25

Cardiopulmonary Support and Physiology Rosenfeldt et al

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In the current era, patients referred for cardiac sur-gery have increasing numbers of risk factors, in-cluding previous angioplasty, myocardial failure,and old age. Age-associated cardiovascularchanges adversely affect the preoperative state ofthe myocardium, rendering it more vulnerable to
stresses1 such as those incurred during cardiac surgery andresulting in higher operative mortality and an increasedincidence of postoperative complications.2,3

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant anda key component of the mitochondrial electron transportchain for adenosine triphosphate (ATP) production.4,5 Myo-cardial CoQ10 content is reduced by cardiac failure andaging.6-8 Further reductions can be caused by 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhib-itors, which have been shown to lower plasma and myocar-dial levels of CoQ10.9-12 Our previous experimental workhas shown that CoQ10 has the ability to protect the myo-cardium against ischemia-reperfusion injury8 and againstaerobic pacing stress, especially in elderly hearts.13

Previous clinical trials have suggested that treatmentwith CoQ10 before cardiac surgery might improve postop-erative cardiac function and reduce myocardial structuraldamage.14-19 However, many of these trials were limited byinsufficient CoQ10 dosage or low patient numbers or werenot randomized, double-blinded, and placebo controlled.Although some of these studies demonstrated increasedserum levels, incorporation of CoQ10 into the myocardiumand mitochondria was not studied. Thus the aim of thepresent study was to perform a prospective, randomized,double-blind trial of preoperative high-dose CoQ10 therapy(300 mg/d) in patients undergoing elective cardiac surgeryon bypass to measure the effect of high-dose CoQ10 therapyon the following: (1) CoQ10 levels in serum, atrial myocar-dium, and mitochondria (dose efficacy); (2) mitochondrialrespiration; and (3) capacity to protect atrial trabeculaeagainst a standard hypoxia-reoxygentation stress in vitro(primary end point). We also sought to assess the effect ofCoQ10 therapy on postsurgical recovery of cardiac pumpfunction, troponin release, and quality of life (secondary endpoints).

MethodsPatient EnrollmentPatients presenting for elective first-time coronary artery bypassgraft or valve operations with cardiopulmonary bypass betweenMay 1998 and July 2000 at the Alfred Hospital were eligible forinclusion in the study. Exclusion criteria were reoperation, urgentor emergency procedures, current therapy with warfarin or anti-oxidants, and recent myocardial infarction (�6 weeks before theoperation).

Patients undergoing elective coronary bypass surgery who pro-vided informed consent were randomized (random numbers in
blocks of 4) to receive either oral CoQ10 (300 mg/d) or placebo in
26 The Journal of Thoracic and Cardiovascular Surgery ● Janua

a double-blinded fashion before the operation, commencing at thetime they were placed on the preoperative waiting list. The studyprotocol was approved by The Alfred Hospital Human EthicsCommittee.

Atrial Appendage Harvest and DissectionAtrial appendages discarded during atrial cannulation before car-diopulmonary bypass were stored in bicarbonate buffer (NaCl,125.8 mmol/L; KCl, 3.6 mmol/L; MgSO4, 0.6 mmol/L; NaH2PO4,1.3 mmol/L; NaHCO3, 25.0 mmol/L; glucose, 11.2 mmol/L; andCaCl2, 2.5 mmol/L equilibrated with 95% O2 and 5% CO2 to pH7.4) containing 30 mmol/L 2,3 butanedione monoxime. All tra-beculae were dissected out for isolation of mitochondria, and up to6 pectinate trabeculae (�1 mm in diameter, �7 mm in length) perpatient were selected for isometric contraction experiments.

Mitochondrial Isolation and RespirationMitochondria were isolated from atrial trabeculae according topreviously reported methods.20 Mitochondrial O2 consumptionwas measured by using a miniature, custom-designed, Clarke-typeO2 electrode in a glass chamber maintained at 37°C. Digital dataacquisition and consumption rate analyses were performed withcustomized software. Mitochondria were suspended in sucrosebuffer (0.3 mol/L sucrose, 5 mmol/L KH2PO4, 5 mmol/L 3-(N-morpholino)propanesulfonic acid (MOPS), 1 mmol/L ethylenedi-amine tetraacetic acid, and 0.1% bovine serum albumin–fatty acidfree) and were added to the glass chamber at a protein concentra-tion of 1 mg/mL. Pyruvate-malate (2.5 mmol/L and 0.5 mmol/L,respectively) was used as a source of electrons for the respiratorychain, whereas 0.34 mmol/L adenosine diphosphate (ADP) wasused to release the accumulation of electrons and drive ATPsynthesis at Complex V. The proton uncoupler carbonyl cyanidep-trifluoromethoxyphenylhydrazone (FCCP) (1 �mol/L) was usedto determine the maximum O2 consumption rate. Sodium cyanide(10 mmol/L) was used to block mitochondria-specific O2 con-sumption at the conclusion of each experiment.

CoQ10 and Malondialdehyde AssaysTotal CoQ10 was measured by means of UV spectrophotometrichigh-performance liquid chromatography analysis after solventextraction of serum or isolated membranes with a mixture ofhexanes and ethanol (1:5:2). CoQ10 (5 �g per sample) was used asthe internal standard to determine the extraction efficiency. Sam-ples and standards were measured on Waters high-performanceliquid chromatography at 280 nm (20 minutes’ run time) by usinga 39:35:26 mixture of methanol, isopropanol, and acetonitrile asthe isocratic mobile phase through a C18 Radial Pak, 8 mm innerdiameter, 4-�m particle column (Waters). CoQ6 and CoQ10 stan-dards (Sigma) ranged from 0.25 to 4 �g and 0.1 to 1.0 �g,respectively. The areas under the peaks of the samples werecompared with those of the standards to determine CoQ10 content.Values were adjusted to the efficiency of CoQ6 extraction andwere expressed as micrograms of CoQ10 per milligrams of mito-chondrial protein or micrograms of CoQ10 per milliliters of serum.

Malondialdehyde (MDA) formation in isolated mitochondrialmembranes was measured spectrophotometrically as an index ofthe degree of lipid peroxidation. A commercial colorimetric assay
(catalog no. 437634, Calbiochem) was used to specifically mea-
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sure the condensation between one molecule of MDA with 2molecules of N-methyl-2-phenylindole to yield a stable chro-mophore at 586 nm.

Atrial Trabecular Function in VitroTrabeculae were attached to organ bath force transducers and werestimulated electrically at 2 Hz in oxygenated bicarbonate buffer, aspreviously described.21 After baseline measurements of contrac-tility, hypoxia was induced by replacing the 95% O2/5% CO2 inthe organ bath with 95% N2/5% CO2. After 30 minutes of hypoxia(PO2, 45 � 3 mm Hg), the trabeculae were reoxygenated, andcontractile recovery was continuously measured. Posthypoxic re-covery of developed force (at 30 minutes) was expressed as apercentage of the prehypoxic value. Measurements were also madeof resting force, time to peak contraction, and time to 50% relax-ation of peak force.

Clinical ProceduresBlood samples were taken for the measurement of CoQ10 levelsbefore and after therapy (in the operating room before cardiopul-monary bypass). Coronary bypass surgery was performed by usinga standard on-pump surgical technique. Myocardial preservationwas attained by means of either intermittent tepid blood cardio-plegia with St Thomas’ potassium-magnesium solution containing15 mmol/L aspartate at 20°C to 25°C (3 surgeons) or by means ofcold crystalloid St Thomas’ cardioplegia at 4°C with topical cool-ing (3 surgeons). Blood samples were taken for measurement oftroponin I levels 4 and 24 hours after admission to the intensivecare unit.

Hemodynamic MonitoringA pulmonary artery thermodilution catheter (Edwards Lifescience)was inserted before the operation for measurement of pulmonarycapillary wedge pressure and cardiac output. Measurements weretaken in the operating room before cardiopulmonary bypass andafter bypass just before closure of the sternotomy and again in theintensive care unit 4 hours after cardiac surgery. Heart rate andmean arterial blood pressure were also recorded and used tocalculate left ventricular stroke work index. Inotropic drug therapywas instituted according to standardized criteria.

Quality-of-life MeasuresThe Medical Outcome Study Short Form 36-item health statusquestionnaire (SF36) was used to assess the quality of life after theoperation. The SF36 is a self-administered questionnaire that as-sesses 8 variables related to physical and mental state, includingfunctional status, emotional and social well-being, and overallevaluation of health.22 The survey was sent to all patients, andreplies were obtained in the first cohort of 60 patients at a medianof 27 months. The physical function parameters were combined toproduce a Physical Component Summary, and the mental functionparameters were combined to produce a Mental Component Sum-mary.

StatisticsSample size calculations showed that to detect a 10% between-group difference in the posthypoxic recovery of pectinate trabec-
ulae developed force with a power of 80% and a significance level
The Journal of Thorac

of .05 would require 94 patients per group. To detect a 15%difference would require 48 patients per group. Variables areexpressed as means � SEM. Log transforms were used to normal-ize length of stay and troponin levels. The t test was used forbetween-group differences in patient demographics, operativevariables, CoQ10 levels, trabecular contractile function, and qual-ity-of-life scores. The �2 and Fisher exact tests were used forcategoric variables. Multivariable analysis was used to test for theinfluence of preoperative variables on recovery of trabecular con-tractile function and troponin I release and for the influence ofpreoperative and operative variables on length of hospital stay.Values are reported as means � SEM unless otherwise stated.Statistical significance was defined as P � .05.

ResultsClinical VariablesOne hundred twenty-one patients were enrolled in the study.There were no significant differences at baseline betweenthe 2 treatment groups (Table 1). The mean length oftreatment in each group was approximately 2 weeks. Theoperative procedures were similar in both groups (Table 2),being predominantly coronary artery bypass graft surgery orvalve replacement. The 6 operating surgeons were distrib-uted equally between the 2 groups (P � .85). There were nodeaths in the hospital.

In Vitro ResultsCoQ10 levels. At baseline, serum CoQ10 levels were

similar in both groups (Table 3). After therapy, serumCoQ10 levels in the CoQ10 group were approximately 4times greater than those in the placebo group (P � .001). Inatrial myocardium the CoQ10 concentration was 2.5 timeshigher in the CoQ10 group than in the placebo group (P �

TABLE 1. Patient demographics and length of therapyPlacebo(n � 59)

CoQ10

(n � 62) P value

Age (y)* 68 (60–74) 67 (56–73) .31Male (%) 85 76 .32Remote MI (%) 43 31 .23LV function grade 2.2 � 0.1 2.1 � 0.1 .68Hypertension (%) 62 57 .63Diuretic (%) 21 10 .13ACE inhibitor (%) 41 26 .11�-blocker (%) 38 50 .23Days of therapy 13.5 � 1.5 14.0 � 1.1 .83

Left ventricular function was graded from the angiographic ejection frac-tion on a 4-point scale: 1, normal (ejection fraction �60%); 2, mildlyimpaired (ejection fraction 46% to 60%); 3, moderately impaired (ejectionfraction 30% to 45%); 4, severely impaired (ejection fraction �30%).CoQ10 , Coenzyme Q10; remote MI, myocardial infarction more than 2months before surgical intervention; LV, left ventricular; ACE, angiotensin-converting enzyme.*Median (50% confidence limits).

.0001). The mitochondrial CoQ10 concentration was 2.4

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times greater in the CoQ10 group than in the placebo group(P � .0002).

Mitochondrial respiration and lipid peroxidation.Coupled oxygen consumption (state III) in isolated myocar-dial mitochondria was significantly lower in the CoQ10

group (49.0 � 2.7 vs 72.2 � 3.7 ng O atoms · min�1 · mg�1

protein, P � .011) than in the placebo group (Figure 1,A).The amount of oxygen consumed after addition of 0.34mmol/L ADP was used to calculate the ADP/O ratio aftercorrection for contaminating adenosine monophosphate.This is a stoichiometric index of the amount of ATP pro-duced (ADP consumed) per mole of oxygen used and isindicative of efficiency in ATP production. For the CoQ10

group, the ADP/O ratio (2.04 � 0.2) was significantlyhigher than for placebo group mitochondria (1.17 � 0.2; P� .012; Fig 1, B). Fig 1, C, demonstrates significantly loweraccumulation of the lipid peroxidation product MDA inmitochondrial membranes in the CoQ10 group (0.9 � 0.04nmol/mg protein) than in the placebo group (1.6 � 0.12nmol/mg protein, P � .002).

Trabecular contractile function. At baseline, therewere no differences in developed force, resting force, ortime to 50% relaxation between the groups (Table 4). Afterhypoxia and reoxygenation, the recovery of developed forcein the CoQ10 group (64.0% � 2.9%) was greater than in the

TABLE 2. Operative variablesPlacebo(n � 59)

CoQ10

(n � 62) P value

CABG alone (%) 93 87 .43Mean grafts 2.9 � 0.1 3.2 � 0.1 .17CPB time (min)* 91 (70–107) 91 (75–106) .61CC time (min)* 57 (42–73) 56 (47–75) .77TBC 39 (66%) 43 (69%) .85

CoQ10 , Coenzyme Q10; CABG, coronary artery bypass grafting; CPB, car-diopulmonary bypass; CC, crossclamp; TBC, tepid blood cardioplegia.*Median (50% confidence limits).

TABLE 3. Serum, atrial myocardium, and mitochondrialCoQ10 levelsCoQ10 measure Placebo CoQ10 P value

Serum baseline* 0.38 � 0.02 0.39 � 0.02 .98Serum after therapy 0.42 � 0.03 1.59 � 0.06 .001Myocardium after therapy† 17.2 � 1.4 43.7 � 3.1 .0001Mitochondria after therapy‡ 4.04 � 0.71 9.53 � 0.90 .0002

CoQ10 , Coenzyme Q10.*The normal range of serum CoQ10 in healthy individuals is 0.5 to 1.0 �g/mL.CoQ10 units are given for serum as micrograms per milliliter, for atrialmyocardium as micrograms per gram of wet weight, and for atrial mito-chondria as micrograms per milligram of protein.†Placebo, n � 56; CoQ10, n � 51.‡Placebo, n � 10; CoQ10, n � 10.

placebo group (46.3% � 4.3%, P � .001, Figure 2). There


were no between-group differences in resting force or timeto 50% relaxation (Table 4). Multivariate analysis identifiedonly treatment group as a predictor of recovery of devel-oped force.

Clinical ResultsHemodynamics. Preoperative hemodynamic perfor-

mance was similar for both groups, as were hemodynamicmeasurements in the operating room after discontinuation ofbypass and stabilization (Table 5). Comparing postbypassvalues with prebypass values across both groups showed anincrease in heart rate (median, 65 beats/min [50% confi-dence limit, 55-76 beats/min] to 90 beats/min [85-95 beats/min], P � .001), an increase in cardiac index (from 2.6 L ·

Figure 1. A, Coupled O2 consumption state III respiration in iso-lated human mitochondria during oxidation of pyruvate (2.5mmol/L) plus malate (0.5 mmol/L) at 37°C. B, The efficiency ofenergy production expressed as a stochiometric ratio of ADPconsumed during ATP production per atom of oxygen consumed.C, The concentration of the lipid peroxidation product MDA inisolated human mitochondria.

min�1 · m�2 [2.1-3.0 L · min�1 · m�2] to 3.0 L · min�1 ·

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m�2 [2.7-3.4 L · min�1 · m�2], P � .001); a reduction instroke work index (from 31 g.m/m2 per beat [29-39 g.m/m2

per beat] to 29 g.m/m2 per beat [23-34 g.m/m2 per beat], P� .003), and a reduction in systemic vascular resistance(from 1187 dynes/s [993-1428 dynes/s] to 886 dynes/s[773-1012 dynes/s], P � .001). However, there were nobetween-group differences in postbypass versus prebypassvalues, except for a decrease in systemic vascular resistancethat was greater in the placebo group than in the CoQ10

group (P � .029). We tested for an effect of cardioplegiatype on postbypass to prebypass hemodynamics. There wasno effect on any of the parameters measured. Also, 4 hoursafter surgical intervention, there was no difference betweentreatment groups in any of the individual hemodynamicmeasurements. The incidence of inotropic drug use in the 2groups was not significantly different (CoQ10 group, 24%;placebo group, 33%; P � .39).

Troponin I release. Troponin I release measured 4hours after the operation was 43.3 � 1.2 �g/L in the CoQ10

group and 44.2 �1.2 �g/L in the placebo group (P � .87),and after 24 hours, it was 14.1 � 1.2 �g/L in the CoQ10

group and 13.6 � 1.2 �g/L in the placebo group (P � .64).Univariate analysis of the determinants of troponin releaseover the 2 time points indicated significant influences ofsurgeon’s technique and operation type but not age orCoQ10 treatment (Table 6). It was not possible to separatethe effect of surgeon’s technique from cardioplegia typebecause each surgeon used only one type of cardioplegia:surgeons 1, 4, and 5 (n � 48) used crystalloid cardioplegia,and surgeons 2, 3, and 6 (n � 73) used blood cardioplegia.Troponin release was significantly higher (P � .0001) in thecold crystalloid cardioplegia user group (35.0 � 1.2 �g/L)than in the tepid blood cardioplegia user group (17.2 � 1.2�g/L). The 2 types of cardioplegia were equally distributedbetween the 2 treatment groups and were therefore unlikelyto have influenced the CoQ10 effect. Multivariate analysisshowed significant influences on troponin I release of sur-geon’s technique, operation type (coronary bypass versus

TABLE 4. In vitro contractile function of isolated atrialtrabeculae

Placebo(n � 20)

CoQ10

(n � 26) P value

Developed forceBaseline (g) 1.02 � 0.12 1.16 � 0.07 .31After hypoxic recovery (%) 46.3 � 4.3 64.0 � 2.9 .001

Resting forceBaseline (g) 0.4 � 0.04 0.5 � 0.06 .18After hypoxic recovery (%) 92.0 � 6.2 86.7 � 2.5 .49

Time to 50% relaxationBaseline (ms) 104.2 � 5.9 104.5 � 3.7 .96After hypoxic recovery (%) 89.1 � 7.1 85.2 � 2.4 .85

CoQ10 , Coenzyme Q10.

valve procedure), and bypass time.


Length of hospital stay. The median postoperativelength of stay in the CoQ10 group was 7.0 days (interquartilerange, 5.0-9.0 days), and in the placebo group, the medianstay was 6.0 days (interquartile range, 5.0-8.0 days). Sig-nificant univariate predictors of postoperative hospitallength of stay were age (r2 � 0.07, P � .0035), cardiopul-monary bypass time (r2 � 0.11, P � .0002), and crossclamptime (r2 � 0.08, P � .0013) but not CoQ10 treatment (r2 �0.002, P � .58). Multivariate analysis showed only age (P� .0027) as a predictor of length of hospital stay.

Late Follow-upAt a median follow-up time of 37 months (interquartilerange, 25-39 months), there were 5 late deaths: 4 (3 non-cardiac and 1 cardiac) in the CoQ10 group and 1 (noncar-diac) in the placebo group (P � .16). Quality-of life assess-ment (SF36 questionnaire) of the first 60 patients at amedian of 27 months (93% complete) showed a signifi-cantly better (�13%) Physical Component Summary in theCoQ10 group (CoQ10 group, 47.5 � 1.6; placebo group,42.0 � 2.1; P � .046 [higher SF36 scores indicate a greaterquality of life]). No significant difference was evident in theMental Component Summary (CoQ10 group, 51.2 � 1.3;placebo group, 51.3 � 1.1; P � .92).

DiscussionCardiac surgery involves multiple stresses to the myocar-dium that contribute to cellular energy depletion. In theintraoperative period there is ischemia-reperfusion injurycaused by aortic crossclamping. In the postoperative periodthere is hypoxia caused by respiratory insufficiency and

Figure 2. Contractile recovery of developed force in atrial pecti-nate trabeculae after 30 minutes of hypoxia.

aerobic stress (high oxygen-demand stress) caused by post-


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operative tachyarrhythmias, such as atrial fibrillation. Theeffect of these stresses is further augmented by preoperativerisk factors, such as advanced age, hypertension, and car-diac failure.1,21,23

Animal studies in a variety of models have shown thatacute or chronic treatment with CoQ10 can protect themyocardium against injury induced by ischemia and reper-fusion,24,25 free radicals,26 and calcium overload.27 Wehave previously reported that CoQ10 pretreatment in ratsconfers myocardial protection against the high oxygen-demand stress of rapid pacing, especially in aged individu-als.13 We have also shown that isolated human myocardialtrabeculae obtained from patients aged 34 to 89 years arealso protected against ischemia-reperfusion injury whenpre-exposed to CoQ10 suspension in vitro.8 Moreover, inthis previous study myocardial tissue from elderly individ-uals showed increased susceptibility to injury, and the pro-tective effect of CoQ10 was greatest in these elderly tissues.These in vitro effects of CoQ10 followed rapid uptake ofCoQ10 into sarcolemmal and mitochondrial membranes. Wetherefore postulated that sustained oral administration ofCoQ10 to cardiac patients would increase myocardial and

TABLE 5. Prebypass and postbypass hemodynamicsPrebypass

Placebo CoQ10

HR (beats/min) 68.1 � 2.9 64.4 � 2.MAP (mm Hg) 75.7 � 1.9 73.4 � 1.CVP (mm Hg) 6.9 � 0.6 7.7 � 0.PCWP (mm Hg) 9.4 � 0.6 9.9 � 0.CI (L · min�1 · m�2) 2.6 � 0.1 2.5 � 0.SVR (dynes/s) 1261.6 � 63.4 1143.7 � 49SV (L/min) 75.7 � 3.3 74.5 � 3.LVSWI (g-m/m2 per beat) 34.7 � 1.8 32.3 � 1.

Values are expressed as means � SEM.CoQ10 , Coenzyme Q10; HR, heart rate; MAP, mean arterial pressure; CVP, ceindex; SVR, systemic vascular resistance; SV, stroke volume; LVSWI, left

TABLE 6. Determinants of troponin I release over the first24 hours postoperativelyParameter P value

Univariate predictorsBypass time .013Surgeon’s technique .017Operation type (valve vs CABG only) .041Age .056CoQ10 treatment .83

Multivariate predictorsBypass time .008Surgeon’s technique .0001Operation type .074

CABG, Coronary artery bypass grafting; CoQ10 , coenzyme Q10.

mitochondrial CoQ10 content, improve energy production,


and confer cellular protection against oxidative stress.These benefits at a myocardial level might be detectable interms of improvements in cardiac function and rate ofrecovery in the postoperative period.

In the present study the 2 treatment groups were compa-rable in terms of preoperative risk factors, and both wereelderly (Table 1). Both treatment groups were subjected tothe same intraoperative stresses in terms of duration ofaortic crossclamping time and cardiopulmonary bypass andextent of surgical procedure.

Myocardial Effects of CoQ10 PretreatmentMitochondria isolated from atrial trabeculae exhibited anincreased CoQ10 concentration in the CoQ10 group com-pared with the placebo group and had greater efficiency ofoxygen consumption during energy production. The higherratio of ADP:O seen in the CoQ10 group compared with theplacebo group demonstrated that CoQ10 pretreatment af-forded preservation of more efficient oxidative phosphory-lation (ATP production), which is required to support invitro posthypoxic contractile function and postoperativepump function. Associated with these effects, mitochondrialmembranes from the CoQ10 group contained reduced levelsof the lipid peroxidation product MDA compared withplacebo, which indicates increased resistance to oxidativeinjury consistent with higher levels of CoQ10 in these mem-branes. These effects demonstrate the multiple molecularroles of CoQ10, in particular as an electron carrier, transfer-ring electrons from nicotinamide adenine dinucleotide(NADH) dehydrogenase and succinate dehydrogenase tothe cytochromes in the inner mitochondrial membrane dur-ing oxidative phosphorylation and as a free radical scaven-ger that inhibits lipid peroxidation.14,24

More recently, it has been shown that CoQ10 also spe-cifically binds to a site in the inner mitochondrial membranethat inhibits the mitochondrial permeability transitionpore.28 The mitochondrial permeability transition pore is a

Postbypass

P value Placebo CoQ10 P value

.15 92.0 � 1.9 90.3 � 1.4 .44

.18 69.2 � 1.1 69.7 � 1.1 .72

.14 7.7 � 0.6 8.3 � 0.5 .44

.28 9.7 � 0.5 9.7 � 0.4 .99

.44 3.2 � 0.1 3.1 � 0.01 .75

.07 889 � 30 1037 � 90 .08

.39 70.4 � 2.3 70.1 � 3.0 .13

.17 28.5 � 0.9 29.3 � 1.1 .59

venous pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiacicular stroke work index.

15451.1

06

ntral

large conductance channel, which, when opened, can trigger

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the collapse of mitochondrial proton-motive force andmembrane potential, leading to the disruption of ionic ho-meostasis and oxidative phosphorylation in cell death sig-naling pathways, particularly after ischemia and reperfu-sion.29 Protection afforded by CoQ10 from oxidativeinactivation of creatine kinase and other key proteins duringreperfusion is crucial in preserving energy metabolism andcardiac performance.14-19

Atrial trabeculae isolated from CoQ10-pretreated patientssubjected to hypoxia-reoxygenation in vitro demonstratedgreater recovery of developed force compared with placebo.This greater capacity for recovery of contractile functionwas associated with increased CoQ10 content in serum andmyocardium after 2 weeks of oral CoQ10 therapy. Cardiactroponin I release was strongly influenced by the differentsurgeon’s techniques, the type of operation, and the durationof cardiopulmonary bypass but not by preoperative CoQ10

therapy.Of interest was an indication of improved subjective

assessment of physical quality of life (�13%) in the CoQ10

group compared with the placebo group when the firstcohort of 60 patients was followed up 22 months postoper-atively. However, these results should be interpreted withcaution because of the fact that quality-of-life data weremissing on 7% of the patients and that subjective improve-ment in physical quality of life does not necessarily indicateimproved cardiac pump function.

Previous CoQ10 Trials in Cardiac SurgeryPrevious randomized studies of CoQ10 treatment in cardiacsurgery have shown significant effects but are limited bysmall patient numbers (�50).15-20 Of these, 3 studies15,17,18

showed an improvement in postoperative hemodynamics inCoQ10-treated patients. Zhou and colleagues14 showed thatCoQ10 treatment significantly reduced plasma levels ofMDA and creatine kinase (cardiac isoenzyme). Chen andassociates19 showed improved preservation of myocardialultrastructure in CoQ10-treated patients. However, Taggartand coworkers16 reported no benefit of oral CoQ10 pretreat-ment in a study of 20 randomized patients undergoingCABG who received 600 mg of CoQ10 or placebo for 12hours before surgical intervention. This latter result can beexplained in terms of insufficient preoperative treatmenttime. Data from our preliminary studies indicated that de-spite a reasonably rapid increase in the blood CoQ10 levelwithin 24 hours, approximately 1 week of treatment wasrequired to show a significant increase in human myocardialCoQ10 concentration.

Limitations of the StudyThere was no difference between groups in hemodynamicmeasurements made at rest in the operating room before orafter cardiopulmonary bypass apart from a greater decrease
in systemic vascular resistance (before vs after bypass) in

the placebo group, which is probably a chance finding. Also,4 hours after the operation, there were no between-groupdifferences in hemodynamic measurements at rest. In theearly postoperative period, any downward changes in car-diac function tend to be corrected by adjustments made ininotropic drug use by intensive care staff in response toperceived clinical need. Thus a useful indicator of majordifferences in postoperative function is inotropic drug use.However, this might be influenced by therapeutic aggres-siveness by intensive care unit staff. We attempted to min-imize therapeutic variability in our study by introducingfixed criteria for initiation of inotrope therapy in the inten-sive care unit. There was a small but nonsignificant differ-ence in use of inotropic drugs in the 2 treatment groups(CoQ10 group, 25%; placebo group, 33%). Sample sizecalculations showed that it would require a sample size of530 per group for such a difference to reach significance.

There was no effect of CoQ10 on hemodynamics beforeor after surgical intervention. If transesophageal echocardi-ography had been available during the trial, pressure-vol-ume loop measures would have been valuable. Reduction inpostoperative release of troponin I would have been persua-sive evidence of reduced intraoperative myocardial damage.However, any ability of CoQ10 to significantly reduce therelease of troponin I was overshadowed by the confoundinginfluences of cardiopulmonary bypass duration, operationtype, and between-surgeon variation in techniques of surgi-cal intervention and myocardial preservation. Thus greaterpatient numbers would be required to ensure sufficientstatistical power to specifically overcome these confoundingfactors.

Conclusions and Clinical ImplicationsThe important finding of the present study is the ability oforally administered CoQ10 to increase CoQ10 levels in hu-man myocardium and mitochondria. The beneficial actionof augmented CoQ10 levels involves increased protection ofmitochondria and myofilaments against oxidative stress,with the consequent maintenance of efficient energy pro-duction and improved contractile recovery after hypoxia-reoxygenation stress in vitro. To directly test the effect ofCoQ10 on key postoperative patient outcomes, includingmore direct measures of recovery of cardiac performanceand length of hospital stay, requires a well-resourced, large,multicenter trial with adequate statistical power to detectchanges in clinically important end points.

We gratefully acknowledge the assistance of the perfusionistsand operating room and intensive care nurses. We also thank JulieMack, Yi Chen Xiao, and the Alfred Hospital’s Departments ofPharmacy and Biochemical Pathology for their assistance (patientdatabase management, data collation, patient randomization, and
troponin I assays, respectively).


CSP

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Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue